-
review
Gut and Liver, Vol. 6, No. 2, April 2012, pp. 172-187
Epidemiology of Gallbladder Disease: Cholelithiasis and
Cancer
Laura M. Stinton and Eldon A. Shaffer
Division of Gastroenterology, Department of Medicine, Faculty of
Medicine, University of Calgary, Calgary, Canada
Diseases of the gallbladder are common and costly. The best
epidemiological screening method to accurately deter-mine point
prevalence of gallstone disease is ultrasonogra-phy. Many risk
factors for cholesterol gallstone formation are not modifiable such
as ethnic background, increasing age, female gender and family
history or genetics. Conversely, the modifi able risks for
cholesterol gallstones are obesity, rapid weight loss and a
sedentary lifestyle. The rising epidemic of obesity and the
metabolic syndrome predicts an escalation of cholesterol gallstone
frequency. Risk factors for biliary sludge include pregnancy, drugs
like ceftiaxone, octreotide and thiazide diuretics, and total
parenteral nutrition or fasting. Diseases like cirrhosis, chronic
hemolysis and ileal Crohns disease are risk factors for black
pigment stones. Gallstone disease in childhood, once considered
rare, has become increasingly recognized with similar risk factors
as those in adults, particularly obesity. Gallbladder cancer is
uncommon in developed countries. In the U.S., it accounts for only
~ 5,000 cases per year. Elsewhere, high incidence rates occur in
North and South American Indians. Other than ethnicity and female
gender, additional risk factors for gallbladder cancer include
cholelithiasis, advancing age, chronic infl ammatory conditions
affecting the gallbladder, congenital biliary abnor-malities, and
diagnostic confusion over gallbladder polyps. (Gut Liver
2012;6:172-187)
Key Words: Gallstones; Cholecystectomy; Gallbladder polyps;
Gallbladder cancer
INTRODUCTION
Diseases of the gallbladder commonly manifest as gallstones and
gallbladder cancer. To identify risk factors in a given
popu-lation, epidemiological studies must first define the
frequency of disease. Studies employing necropsy surveys or
healthcare
Correspondence to: Eldon A. ShafferDivision of Gastroenterology
(TRW Building), Faculty of Medicine, University of Calgary, 3280
Hospital Drive NW, Calgary, AB, T2N 4N1, CanadaTel: +1-4035925033,
Fax: +1-4035925090, E-mail: [email protected]
Received on October 6, 2011. Accepted on October 20, 2011.pISSN
1976-2283 eISSN 2005-1212
http://dx.doi.org/10.5009/gnl.2012.6.2.172
This is an Open Access article distributed under the terms of
the Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/3.0) which permits
unrestricted non-commercial use, distribution, and reproduction in
any medium, provided the original work is properly cited.
databases carry biases by their implicit nature: being
postmor-tem or requiring biliary symptoms/complications,
respectively.1-3 Another potential measure of disease burden, the
frequency of cholecystectomy, is a limited marker for the
prevalence of gall-stones, as the perceived threshold for surgery
and patient access to care differ greatly.4 Some epidemiological
studies have been confounded by inadequate sample size or selection
bias. Small sample size is open to a beta-II type error: a failure
to accurately identify a true difference (i.e., a false negative
result). Selection bias may lead to spurious differences (i.e., a
false positive result). More reliable epidemiological studies now
use transabdominal ultrasound to screen robust numbers in defined
asymptomatic populations. Ultrasonography is an ideal means to
quantitate the frequency of gallstone disease, being a noninvasive
and safe imaging technique that accurately can detect the point
preva-lence of gallstones in a defined asymptomatic population.
GALLSTONE DISEASE
1. Burden of gallstone disease
Gallstones constitute a significant health problem in devel-oped
societies, affecting 10% to 15% of the adult population, meaning 20
to 25 million Americans have (or will have) gall-stones.2,5-7 The
resultant direct and indirect cost of gallbladder disease
represents a consumption of ~$6.2 billion annually in the U.S.,
constituting a major health burden that has increased more than 20%
over the last 3 decades.2,8,9 With an estimated 1.8 million
ambulatory care visits each year, gallstone disease is a leading
cause for hospital admissions related to gastrointestinal
problems.10 These numbers are likely an underestimate because
laparoscopic cholecystectomy is often performed as a day pro-cedure
and thus not captured by hospital statistics that require overnight
admission. Although the mortality rate for gallstones disease is
relatively low at 0.6%, the high burden of disease imposes
troubling mortality figures, such as an estimated 1,092
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Stinton LM, et al: Epidemiology of Gallbladder Disease:
Cholelithiasis and Cancer 173
gallstone-related deaths for 2004 in the U.S. Fortunately, case
fatality rates have steadily diminished from over 5,000 deaths in
1950, falling >50% between the years 1979 and 2004. This
de-cline represents the greatest decrease for any digestive
disease.9
Gallstone disease per se also carries inherent risks.
Prospective population-based surveys have revealed an increased
overall mortality, particularly from cardiovascular disease and
cancer, as seen in Americans and Pima Indians with
cholelithiasis.11,12
Further, as the incidence of gallstone disease escalates, there
is a concomitant increase in complications like gallstone-related
pancreatitis.13
The number of surgical procedures for cholelithiasis has risen
markedly in developed countries since 1950.14 The introduc-tion of
laparoscopic cholecystectomy in 1989 further increased the
cholecystectomy rate.14-16 From 1990 to 1993, for example, there
was a 28% escalation in the number of cholecystectomies
performed.17 The change in practice emanated from the lapa-roscopic
surgical approach, which represented a less invasive, more
cosmetically acceptable operation while providing a lower surgical
risk compared to the then conventional or open pro-cedure. This
likely resulted in more surgeries being done in pa-tients
previously thought to be too high a risk, or in those with minimal
symptoms. Although there is undoubtedly an element of overuse,
cholecystectomy is now the most common elective abdominal surgery
performed in the U.S., with over 750,000 operations being performed
annually.6,16,18 The cholecystectomy rate, though increased,
fortunately appears to have stabilized in the late 1990s and may
even be on the decline in the U.S.19
2. Clinical aspects of gallstone disease
1) Asymptomatic/Silent gallstones Gallstones are common. 10% to
20% of Americans will
develop stones at some time.20 The majority will not develop
symptoms: up to 80% will never experience biliary pain or
complications such as acute cholecystitis, cholangitis, or
pan-creatitis.21 Hence, most gallstones are clinically silent, an
in-cidental finding often uncovered during abdominal ultrasound
being performed for another reason.22 People with such
asymp-tomatic cholelithiasis, however, eventually may develop
symp-toms (biliary pain) that require treatment,23 but this risk is
quite low averaging 2% to 3% per year,24 10% by 5 years.1,23 An
even lower proportion, 1% to 2% per year, develop major gallstone
complications.20,25 Therefore, expectant management is an
ap-propriate choice for silent gallstones in the general
population. The exception is patients at high risk for experiencing
biliary complications:
(1) Large gallstones (>3 cm) or gallbladders crammed with
stones that carry a higher risk of developing gallbladder cancer,
perhaps an indication for prophylactic cholecystectomy.26,27
(2) Sickle cell disease is associated with the development of
pigment gallstones, frequently necessitating cholecystectomy.
Prophylactic cholecystectomy should be considered because
stone complications is frequently difficult to distinguish from
the clinical features of a sickle cell crisis or its complications
such as infarction of the liver or abdominal viscera.28 When
per-formed early, outside the emergency setting, cholecystectomy
lessens the surgical risks, but still carries a high mortality rate
at 1% and postoperative complications of >30%.29
(3) Solid organ transplantation (heart, lung, kidney, pancreas).
Although stem cell (bone marrow) transplantation carries its own
problems from cholelithiasis and biliary sludge developing, more
problematic is the aftermath of solid organ transplantation in
which gallstones that develop frequently progress to symp-toms and
complications like cholecystitis, principally during the first 2
years.30 Liver transplantation is exempt; the gallbladder is
removed at the time of hepatectomy. Controversy exists in patients
with asymptomatic gallstone disease who are undergo-ing solid organ
transplantation: expectant management with routine screening
ultrasonography vs prophylactic (pre-/post-transplantation)
cholecystectomy.
(4) Abdominal surgery, performed for other reasons, may benefit
from a simultaneous cholecystectomy in situations where the risk of
gallstone formation and complications are high. Prophylactic
cholecystectomy therefore should be consid-ered in morbidly obese
patients undergoing bariatric surgery.31
2) Symptomatic gallstone diseaseSince most gallstones are
asymptomatic, it is essential to
define exactly which symptoms are caused by gallstones: true
biliary pain and/or complications, versus nonspecific abdominal
complaints including dyspepsia.32-34 Gallstone-associated pain
seems to follow a certain pattern in most patients.35,36 Consen-sus
groups have attempted to establish criteria for biliary pain
relative to defined characteristics (e.g., episodic, steady, severe
pain located in the upper abdomen and lasting more than 30 minutes)
and some accompanying features (e.g., nocturnal on-set; nausea and
vomiting; radiating through to the back).11 The importance for
clarifying what constitutes true biliary pain is to better predict
relief following cholecystectomy. Currently, cholecystectomy does
not relieve biliary pain in 10% to 33% of people with documented
gallstones.37,38 Confusion with other functional gut disorders like
irritable bowel syndrome (IBS) and dyspepsia will not provide a
favorable outcome from cholecys-tectomy.39,40 The avoidance of an
unnecessary cholecystectomy becomes critically germane in an era of
escalating rates of sur-gery.
3) Functional (acalculous) gallbladder diseaseBiliary pain
seemingly results from increased intraluminal
pressure as the gallbladder contracts against an obstructed
out-let. In gallstone disease, the obstruction is obvious: a stone
in the cystic duct. In functional gallbladder disease (also termed;
acalculous gallbladder disease, gallbladder dyskinesia or biliary
dyskinesia), the pain mechanism may be obstruction located at
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174 Gut and Liver, Vol. 6, No. 2, April 2012
the gallbladder outlet, incoordination between gallbladder
con-traction and sphincter of Oddi relaxation, or visceral
hypersen-sitivity. A clue to its existence is impaired gallbladder
emptying, reliably quantitated by
cholecystokinin-cholescintigraphy.41,42 Yet the frequency and
management of acalculous gallbladder disease remains unclear.
Eliminating the apparent problem, the gallbladder, via laparoscopic
cholecystectomy is fraught with challenges, particularly in
selecting those who would most benefit. Although the exact
frequency of biliary dyskinesia is unknown, any increase in the
employment of cholecystectomy for such cases most certainly would
impact surgical rates. Thus, there is insufficient evidence to
support a role for cholecystec-tomy in functional gallbladder
disease at this time.43 Hence, patients with suspected functional
biliary pain but whose intact gallbladder lacks ultrasonographic
evidence of gallstones should be carefully evaluated to exclude
other causes for their symp-toms.
3. Risk factors for gallstone formation
Important risk factors have been identified as being associ-ated
with gallstones (Table 1).2 Multiple case-control studies,
comparing those with gallstones versus those without, have shown
that gallstone formation is multifactorial. Some features, such as
ethnicity, genetics, advancing age and female gender cannot be
modified, whereas others (e.g., diet, physical activity, rapid
weight loss and obesity) are modifiable.
1) EthnicityGeography and particularly ethnicity play an
enormous role
in the prevalence of gallstone disease and also the type of
stone that forms: cholesterol gallstones predominate in the
developed countries of the Western world; brown pigment stones in
the bile ducts are more common in Asia (Table 2, Fig. 1).44
North American Indians have the highest reported rates of
cholelithiasis, afflicting 64.1% of women and 29.5% of men.2,45 The
aboriginal populations of South America also have an exceedingly
high prevalence of gallstones: 49.4% of native Mapuche Indians of
Chile women and 12.6% of men harbor gallstones.46 Mexican Americans
are also at heightened risk
when compared to White Americans; however, this risk is
di-rectly related to the degree of Amerindian admixture.47-50 White
Americans have an overall prevalence of 16.6% in women and 8.6% in
men.6,47 Intermediate prevalence rates occur in Asian
populations51,52 and Black Americans (13.9% of women; 5.3% of
men).6 The lowest frequencies occur in sub-Saharan Black Africans
(85%), whereas the remainder constitutes black pigment stones
(i.e., composed of calcium bilirubinate) (Table 2).2,7
The situation differs in East Asia where brown pigment stones
are located in bile ducts, predominately associated with parasitic
infestation. In developed countries, however, these bile duct
stones arise in association with the inflammation and infection
that result from biliary strictures and malignancies. Brown
pig-ment stones consist of some calcium bilirubinate (hence their
dark color), fatty acid soaps (calcium palmitate and calcium
stearate, hence their greasy feel), some cholesterol, and muci-nous
glycoproteins (a product of bacterial biofilms). They form de novo
in the common bile duct (choledocholithiasis) or the intrahepatic
bile ducts (hepatolithiasis). These primary ductal stones result
from bacterial infection, biliary parasites (Clonor-chis sinensis,
Opisthorchis species, Fasciola hepatica) and stasis from partial
biliary obstruction. Brown pigment stones are the predominant type
in Asia where they can cause Oriental chol-angiohepatitis: biliary
obstruction with recurrent cholangitis, dilatation and stricturing
of the biliary tree. In hepatolithiasis, stones are present in the
intrahepatic bile ducts, regardless of any coexistent stones
residing elsewhere in the biliary system (i.e., the extrahepatic
ducts or the gallbladder). The brown pig-ment stones that arise in
intrahepatic sites (hepatolithiasis) pos-sess relatively more
cholesterol and less bilirubin than those that form in extrahepatic
sites, presumably due to a different mecha-nism for their
formation. The frequency of hepatolithiasis, as a proportion of all
bile duct stones, is as high as 20% in China and Taiwan, yet as low
at 2% to 3% in Japan, Singapore, and Hong Kong.54 The stone type
curiously has recently shifted in developing Asian countries from
pigment to cholesterol stones. The basis for this change may
reflect a decreased rate of chronic
Table 1. Risk Factors for Gallstone Disease
Not modifiable Modifiable
Family history Obesity/metabolic syndrome/diabetes
mellitus/dyslipidemia
Genetic predilection Drugs ceftriaxone, octreotide, thiazide
diuretics, female sex hormones
Ethnic background Reduced physical activity
Female sex Rapid weight loss
Age TPN
Diet
Underlying disease: cirrhosis, Crohns disease
TPN, total parental nutrition.
-
Stinton LM, et al: Epidemiology of Gallbladder Disease:
Cholelithiasis and Cancer 175
biliary infections and consumption of a more Westernized
diet.2
2) Family history & genetics Genetic susceptibility is a key
factor in gallstone formation.55
Familial studies reveal an increased frequency: a nearly 5 times
elevated risk in the relatives of gallstone patients. These rate
are even higher in monozygotic twins at 12% and dizygotic twins at
6%.56,57 Yet spouses of affected patients do not have any increased
risk, thereby eliminating a shared environment as the basis - i.e.,
similar dietary and other common habits among family members as the
explanation for this apparent associa-tion.58 In a Swedish twin
study, genetic effects accounted for
25%, shared environmental influences for 13% and unique
en-vironmental effects for 62% of the phenotypic variance.59
No mode of simple Mendelian pattern of inheritance can ac-count
for the majority of cases with gallstone disease. In fact, stone
formation is a complex interaction of genes and environ-mental
factors, particularly diet-gene interactions.55,60 Several genes
have been associated with gallstone disease.61 Identified so far
have been: the apolipoproteins E (APOE) and B (APOB),62
cholesterol ester transporting protein (CETP), cholesterol 7
-hydroxylase,63 cholecystokinin receptor A (CCKAR),64 the LDL
receptor (LDLR)65 and the CETP.66 Genome-wide association analysis
has revealed that variants for the hepatic cholesterol
Table 2. Types of Gallbladder and Biliary Tract Stones:
Characteristics and Clinical Associations
Cholesterol gallstones Black pigment stones Brown pigment stones
Biliary sludge (microlithiasis)
Composition Cholesterol (50-100%) Calcium bilirubinate polymer
Unconjugated bilirubin, calcium soaps of fatty acids, cholesterol
& mucin
Pigment (calcium-bilirubi-nate), cholesterol microcrystals &
mucin
Location Gallbladdercommon duct (~10%)
Gallbladdercommon duct
Bile ducts Gallbladder
Detection Ultrasonography Ultrasonography Cholangiography
Abdominal or endoscopic ultrasonography; microscopy of bile
Clinical associations Metabolic: family history (genetic
traits), obesity, female sex, aging[excessive cholesterol
secretion]
Increased or altered bilirubin excretion in hemolysis,
cir-rhosis, cystic fibrosis, Crohns disease, advanced age[excessive
bilirubin excretion]
Infection, inflammation,infestation [stasis, strictures]
Fasting, TPN, pregnancy-possible prelude to stone formation
TPN, total parental nutrition.
Fig. 1. Worldwide prevalence of gallstones in females based on
ultrasonographic surveys varies.45 Prevalence is inordinately high
in American Indians and their admixtures, and also Northern
Europeans; somewhat lower in European and American whites;
intermediate in Asians and black Americans, and quite low in black
Africans.
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176 Gut and Liver, Vol. 6, No. 2, April 2012
secretion (ABCG8 19H and ABCB4) represent a susceptibility
factor for human gallstones.67,68 Conferring an odds ratios of 2 to
3 for heterozygous and 7 for homozygous carriers, these vari-ants
account for 11% of the total gallstone risk. Such human
susceptibility (gallstone) genes therefore are not common and so
embody a rather modest contribution. Cholelithiasis most likely is
a polygenetic disease entity.
3) AgeThe frequency of gallstones increases with age,
escalating
markedly after age 40 to become 4 to 10 times more likely in
older individuals.2,69 The stone type also changes with age:
initially being composed predominantly of cholesterol
(corre-sponding to an increased cholesterol secretion into and
satura-tion of bile) but in late life tending to be black pigment
stones. Further, symptoms and complications increase with age,
leading to more frequent cholecystectomies.70
4) Gender and female sex hormonesThe female gender has a most
compelling association with
gallstone disease, especially during the fertile years. Women
are almost twice as likely as men to form stones; the gap narrows
following menopause after which men begin to catch up.2 The
underlying mechanism is female sex hormones; parity, oral
con-traceptive use and estrogen replacement therapy are established
risk factors for cholesterol gallstone formation.71-73 Female sex
hormones adversely influence hepatic bile secretion and
gall-bladder function. Estrogens increase cholesterol secretion and
diminish bile salt secretion, while progestins act by reducing bile
salt secretion and impairing gallbladder emptying leading to
stasis. A new 4th generation progestin, drospirenone, used in some
oral contraceptives may further heighten the risk of gall-stone
disease and cholecystectomy; however, the increased risk is quite
modest and not likely to be clinically meaningful.74
During pregnancy when female sex hormones are endog-enously
raised, biliary sludge (particulate material that is com-posed of
cholesterol, calcium bilirubinate, and mucin) appears in 5% to 30%
of women. Resolution frequently transpires dur-ing the post-partum
period: sludge disappears in two-thirds; small (32 kg/m2) showed an
age-adjusted relative risk of 6.0 for the development of gallstones
compared with nonobese controls; their annual incidence of
developing gallstones is 2%.85 Obesity is associated with an
increased activity of the rate-limiting step in cholesterol
synthesis, the hepatic enzyme, 3-hydroxyl-3-methyl-glutaryl
co-enzyme A (HMG-CoA) reductase, leading to increased cho-lesterol
synthesis in the liver and its heightened secretion into
bile.80,86,87
6) Dyslipidemia, diabetes mellitus and the metabolic
syn-drome
Cholesterol gallstone disease is a metabolic problem, which
correlates with lipid abnormalities, diabetes mellitus and
adipos-ity. A low HDL cholesterol88 and hypertriglyceridemia89,90
carry an increased risk of developing stones. In contrast, there is
no definite association with hypercholesterolemia.2,91 High
homo-cysteine levels also may correlate with gallstone
disease.92
The metabolic syndrome is defined by the presence of at least 3
features out of: abdominal obesity, high blood pressure, high
fasting glucose, increased triglyceride levels and reduced HDL
levels.93,94 Both the metabolic syndrome and diabetes mellitus are
risk factors for gallstone disease.95 The metabolic syndrome has
also been associated with stone complications.96 Insulin resistance
predisposes to cholesterol gallstone formation,97,98 suggesting
altered cholesterol and bile salt metabolism. Hepatic insulin
resistance may act by enhancing hepatic cholesterol se-cretion,
depressing bile salt synthesis and/or impairing gallblad-der
motility.99-101
7) Rapid weight lossLow caloric diets and/or bariatric surgery
with rapid weight
loss are associated with gallstones developing in 30% to 71% of
such individuals.102-108 Weight loss that exceeds 1.5 kg/wk
fol-lowing bariatric surgery increases the risk for stone
formation; these stones are most likely to become apparent during
the first 6 weeks after surgery when weight loss is most
profound.109,110 Weight loss-associated gallstones are typically
asymptomatic; only 7% to 16% develop symptoms, best predicted by a
postop-erative weight loss exceeding 25% of the body weight.84 Even
less extreme weight fluctuations create a risk for stone
forma-tion,111 as is a history of dieting.112
8) Diet and total parental nutrition (TPN)Other than a high
caloric intake that leads to obesity, any
importance of the dietary content is unclear and difficult to
analyze.113-115 Diets specifically high in cholesterol,116 fatty
ac-ids,117 carbohydrates118,119 or legumes120 seem to increase the
risk of cholelithiasis. In contrast, unsaturated fats,121
coffee,122,123 fiber,124,125 ascorbic acid (vitamin C),126,127
calcium114 and moder-
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Stinton LM, et al: Epidemiology of Gallbladder Disease:
Cholelithiasis and Cancer 177
ate consumption of alcohol118,124,128 reduce the risk.
Certainly, the shift to a more Western diet, high in refined
carbohydrates and fat (triglycerides) and low in fiber, best
explains the profound increase in cholesterol gallstones amongst
American Indians (unmasking their presumed genetic burden) and in
European countries following World War II. This dietary change also
might account for the shift from pigment to cholesterol stones in
Asian countries2,129,130 Genetic variations, especially in the
genes that control cholesterol metabolism, might underscore why
some respond to dietary change by developing cholesterol
gallstones.16,60
TPN is a well-known risk factor for developing microlithia-sis
(biliary sludge) and gallstone disease, in addition to acute
acalculous cholecystitis in critically ill patients.131-134 In an
in-tensive care setting, biliary sludge appears after 5 to 10 days
of fasting.17,49 After 4 weeks of TPN, half of those on TPN develop
gallbladder sludge on ultrasonography; after 6 weeks all show
evidence of sludge.135 Most are asymptomatic. Fortunately, sludge
resolves within 4 weeks of discontinuing TPN and re-suming an oral
intake, a pattern similar to sludge appearing during pregnancy and
rapid weight loss and then disappearing once the inciting event
resolves.136 A possible explanation for this relates to loss of the
enteric stimulation of the gallbladder in the absence of eating,
leading to gallbladder stasis.134 Addition-ally, ileal disorders
such as Crohns disease or ileal resection, in which TPN is
frequently required, can affect the enterohepatic cycling of bile
acids and so augment bilirubin absorption and subsequent hepatic
excretion.86
9) Lifestyle factors and socioeconomic statusThe exact role of
socioeconomic status and gallstones is con-
troversial.2 A previous cross-sectional study of non-Hispanic
Whites and Mexican Americans, found gallbladder disease inversely
related to socioeconomic status.137 Socioeconomic status, however,
may merely be an indirect marker for other risk factors like
obesity and chronic medical conditions. The role of smoking in
cholelithiasis is unclear.138
Reduced physical activity heightens the risk of gallstone
disease whereas increased physical activity helps prevent
cho-lelithiasis, independent of its role in weight loss.122,139
Increased endurance exercise (to 30 minutes 5 times a week) may
avert symptomatic gallstones developing in men.140
10) Underlying chronic diseases(1) Liver disease Advanced
cirrhosis is a well-established risk factor for gall-
stones, with an overall prevalence at 25% to 30%.141-143 Usually
the stones consist of the black pigment type in patients with
cirrhosis.144 This is likely related to altered pigment secretion,
abnormal gallbladder motility and/or increased estrogen levels.2
Gallstone disease is also associated with chronic hepatitis C viral
infection and nonalcoholic fatty liver disease;145-147 other
factors
for this are the metabolic syndrome and obesity.148
(2) Crohns diseaseThere is a two-three fold increased risk of
developing gall-
stones in patients with extensive ileal Crohns disease.77,149 An
obvious explanation for this is ileal disease or loss leading to
bile acid malabsorption and depletion, reduced hepatic secretion of
bile acids and bile that is supersaturated with cholesterol,
leading to cholesterol stone formation. The cholesterol content in
bile however can be rather normal or even low in these
pa-tients.150 Instead, there appears to be an increased frequency
of pigment stones. Failure of terminal ileal transport in Crohns
disease allows excess bile acids to escape into the colon, where
these biological detergents solubilize unconjugated bilirubin and
so facilitate their absorption and return to the liver. The liver
then secretes excessive pigment that subsequently pre-cipitates as
gallstones.151 Other explanations include fasting in patients with
Crohns disease, or altered bacterial colonic flora that enhance the
deconjugation of bilirubin, which can then be passively absorbed;
the result is an upregulated enterohepatic cycling of bile
pigment.152
(3) Cystic fibrosisSimilar to ileal Crohns disease, cystic
fibrosis is associated
with bile acid malabsorption due to its binding to undigested
dietary nutrients. Gallstone prevalence in cystic fibrosis is
in-creased 10% to 30%.153
(4) Other diseasesIn sickle cell disease, chronic hemolysis
leads to excessive
bilirubin excretion with the formation of black pigment stones
composed of calcium bilirubinate. These tend to be small in size,
permitting some to travel into the common duct; the resultant
obstruction is low-grade, not necessarily accompanied by duct
dilation or cholangitis. Due to potential complications and the
difficulty in distinguishing biliary-type pain from other
com-plications of sickle cell disease, prophylactic cholecystectomy
should be considered.29
Spinal cord injury is associated with a threefold increase in
gallstone formation.154-156 Possible explanations for this include
gallbladder stasis with sludge formation and intestinal
hypomo-tility that alters bile acid metabolism.
IBS presents with abdominal pain in addition to other fea-tures,
perhaps fostering cholecystectomy as a more common operation in
patients with IBS. This may reflect inappropriate surgery caused by
diagnostic confusion157 or post-surgical IBS symptoms as a
consequence of the operation.158
11) Drugs(1) OctreotideOctreotide, a long-acting analogue of
somatostatin that
inhibits cholecystokinin release, results in decreased
gallblad-der motility and stasis.159 Inhibition of cholecystokinin
also depresses small intestine motility; the resultant intestinal
stasis enhances the formation of secondary bile acids like
deoxycho-
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178 Gut and Liver, Vol. 6, No. 2, April 2012
lic acid. Deoxycholic acid adversely influences bile formation
(increasing cholesterol secretion) and augments the synthesis of
gallbladder mucin (important for the precipitation of choles-terol
microcrystals from bile and their subsequent growth into stones).
Greater than 50% of patients receiving octreotide ac-cordingly will
develop cholelithiasis, although the majority are
asymptomatic.160,161
(2) CeftriaxoneCeftriaxone, a third generation cephalosporin
antibiotic, is
secreted unmetabolized into bile, achieving high
concentra-tions.86 This can result in biliary sludge and
pseudolithiasis in those patients, particularly children, receiving
ceftriaxone. Most remain asymptomatic. Meanwhile, the sludge
resolves once the medication is discontinued.162,163
(3) Thiazide diuretics Thiazide treatment may increase biliary
cholesterol saturation
leading to gallstones developing.164 Some case-controlled
reports have suggested that thiazide use is associated with a
heightened risk of acute cholecystitis.165,166 Others have not
found any as-sociation.140 Most likely, thiazide use conveys a
modest effect. In one prospective study concerning women taking
thiazide diuretics, the relative risk of cholecystectomy rose 36%
for past users and 57% for current users.167
(4) StatinsDrugs that inhibit HMG-CoA reductase seem to prevent
cho-
lesterol gallstone disease by diminishing cholesterol synthesis
in the liver and decreasing its secretion into bile.168
12) Gallbladder disease in childrenCholelithiasis in the
pediatric age group has been considered
rare, historically thought to be black pigment stones related to
prematurity and TPN use in infants or chronic hemolysis in
adolescents. Cholesterol stones, in fact, are becoming
increas-ingly more common in children.169-171 In unselected
pediatric populations, the prevalence rates are reported between
0.1% to 1.0%.170,172 One explanation for this increase is greater
access to and use of abdominal ultrasonography in children.173 A
more prominent factor now is obesity, accounting for some 8% to 33%
of gallstones observed in children.174,175 In obese children and
adolescents, the prevalence may be as high as 2.0%.171 Other risk
factors for gallstone disease in childhood include: female gender,
pregnancy and oral contraceptive use; being of Mexican-American
origin; drug exposure to cephalosporins, ceftriaxone or diuretics;
a history of cardiac surgery or bowel resection, and having cystic
fibrosis.149,172,173,176 In fact, the risk factors for pediatric
gallbladder disease now more closely re-semble those in adults.
40% to 51% of children with gallstones are asymptomat-ic.173,177
Those with no symptoms have a lower rate of complica-tions, while
gallstones may resolve in 17%. Therefore conserva-tive management
is recommended in these children. Pediatric patients with
symptomatic cholelithiasis are at risk for compli-
cations (18% to 28%); the most common presentation is right
upper quadrant abdominal pain.173,178 Complications include acute
cholecystitis, choledocholithiasis and pancreatitis.
Laparoscopic cholecystectomy is safe and can be quite effec-tive
in children. Cholecystectomy for children with symptomatic
gallstones therefore is the standard of care. Surgery is also being
used more frequently for functional gallbladder disease (biliary
dyskinesia), an entity that bears scrutiny given the absence of
clear diagnostic criteria or effective management schemes.169
GALLBLADDER CANCER
Gallbladder cancer is a notoriously rare though lethal
malig-nancy with marked ethnic and geographical variations. The
pre-senting symptoms are typically vague so that its diagnosis
com-monly occurs at an advanced stage. This late diagnosis plus the
anatomic feature that the gallbladder lacks a serosa culminates in
a rather dismal prognosis.179-181 The overall mean survival rate
for patients with advanced gallbladder cancer is 6 months, with a
5-year survival rate of 5%.182 Early gallbladder cancer (confined
to the mucosa), though infrequent, offers the potential for a cure
though cholecystectomy. Most (>80%) gallbladder cancers are
adenocarcinomas that originate from the fundus (60%), body (30%),
or neck (10%). The basis likely is genetic susceptibility, perhaps
elicited by chronic gallbladder inflammation, often a product of
cholelithiasis.181,183,184 One reasonable hypothesis fo-cuses on
chronic irritation of the mucosa (e.g., from the physical presence
of the stones and/or superimposed chronic infection such as from
Salmonella typhi) leading to dysplasia (perhaps abetted by
mutagenic secondary bile acids) and terminating in malignant
change.
The risk factors for developing gallbladder cancer therefore
include ethnicity, genetic susceptibility, lifestyle factors and
infections. Elucidating such risk factors (Table 3) not only
pro-vides insight into its pathogenesis accounting for its
geographic and ethnic variances (Fig. 2), but more importantly
should yield strategies to prevent and treat this unusual
malignancy.185
1. Ethnicity, gender, and age
Gallbladder cancer is rare in developed countries. In the U.S.,
it only accounts for 0.5% of all gastrointestinal malignan-cies,
accounting for less than 5,000 cases per year (1 to 2.5 per
100,000).183 Worldwide, gallbladder cancer has a low occurrence
-
Stinton LM, et al: Epidemiology of Gallbladder Disease:
Cholelithiasis and Cancer 179
land), northern India (as high as 21.5/100,000 for women from
Delhi) and south Pakistan (11.3/100,000).185 Intermediate
inci-dences (3.7 to 9.1 per 100,000) occur elsewhere in South
Ameri-cans of Indian descent, and in Israel (5/100,000) and Japan
(7/100,000).184 The frequency is increasing in Shanghai, China and
now accounts for the most frequent gastrointestinal malig-nancy and
is a substantial cause of mortality.188 Although the majority of
the world has decreasing mortality trends in gall-bladder cancer,
Iceland, Costa Rica, and Korea have an increase in mortality for
men.189 There appears to be a modest decline in prevalence over the
past two decades (National Cancer Institute. Surveillance,
Epidemiology and End Results (SEER) Program
[http://seer.cancer.gov/]).
Gender differences exist with geographic variances, generally
being unfavorable for women. In those locals with the highest
incidence, women have frequency rates greater than men. With age,
gallbladder cancer increases.
2. Gallstones
A history of gallstones appears to carry the highest risk for
gallbladder cancer, with a relative risk of 4.9.185 Most (69% to
100%) but not all people with gallbladder cancer have
cho-lelithiasis. Further, these 2 entities frequently co-exist in
the same populations, suggesting that stones may function as a
co-factor for this carcinoma.190 American Indians, who have a quite
high prevalence of cholesterol gallstone disease, also have a high
incidence of carcinoma of the gallbladder; yet in other
settings, there is a low incidence of gallbladder cancer despite
an overall high frequency of cholelithiasis. Increasing stone size
(>3 cm),191,192 number, volume, and weight, all are associ-ated
with an increased risk of cancer.190 Less important is the duration
of cholelithiasis.193 Cholesterol stones seem to be more common
than pigment stones in gallbladder cancer patients.194 Further
attesting to gallstones being a risk factor for gallbladder
carcinoma, the incidence of this cancer rises when the
chole-cystectomy rate declines.184,195 Nevertheless, consensus does
not generally favor prophylactic cholecystectomy for asymptomatic
stones196,197 as cholelithiasis is too common and gallbladder
can-
Table 3. Risk Factors for Gallbladder Cancer
Risk factor Relative risk Reference
Gallstones 3.01-23.8 218-222
Size of gallstones 2.0-2.9 cm >3.0 cm
2.49.2-10.1
191,223
Duration of gallstones 5-19 yr >20 yr
4.96.2
193
BMI 30.0-34.9
Men Women1.8 2.1
215
Infections Chronic typhoid & paratyphoid carriers
Helicobacter bilis
12.7-167
2.6-6.5
224,225
206,226
Fig. 2. Incidence of gallbladder cancer worldwide (From National
Cancer Institute. Surveillance, Epidemiology and End Results (SEER)
Program. Available from http://seer.cancer.gov/). Carcinoma of the
gallbladder is more common in certain ethnic groups: native
American Indians, white Hispanics from North and South America, and
those from northern India and Eastern Europe.198 Elsewhere in the
world, the incidence is low at
-
180 Gut and Liver, Vol. 6, No. 2, April 2012
cer too rare. Potential exceptions include large stones greater
than 3 cm, which have a risk of 4% over 20 years,27,198 and
el-derly American Indian females with gallstones.199
3. Chronic infl ammation
Chronic inflammation from any cause may lead to calcium being
deposited in the gallbladder wall, termed the porcelain gallbladder
because of its bluish color and fragile, brittle con-sistency.200
This entity is rare, being identified pathologically in less than
1% of gallbladder specimens. The calcium depos-its can be detected
on diagnostic imaging - plain abdominal radiographs, ultrasounds or
computed tomography images. Controversy exists whether or not the
porcelain gallbladder is truly associated with an increased risk of
cancer. Some stud-ies indicate that 25% (range, 12% to 61%) are
associated with gallbladder cancer,199,201 whereas more recent
reports negate any such association.202 Only gallbladders with
partial calcification, stippled or multiple punctate calcifications
in the glandular spaces of the mucosa, are premalignant and
therefore should be removed prophylactically. Those with a broad
continuous band of calcification in the muscularis appear not to be
harbingers of gallbladder cancer.
Chronic bacterial infections also cause irritation and
inflam-mation in the gallbladder. S. typhi carriers have an 8 to
12-fold increased risk with 6% developing gallbladder
cancer.203-205 In contrast to typhoid carriers, however, a past
history of typhoid fever is not associated with the development of
gallbladder can-cer.206 Helicobacter pilis is also implicated in
gallbladder cancer with an odds ratio of 6.5 in Japanese patients
and 5.86 in Thai patients.206
Primary sclerosing cholangitis (PSC) is typically associated
with an increased risk of cholangiocarcinoma. As dysplasia oc-curs
in 37% and adenocarcinoma in 14% of gallbladders from patients with
PSC, their general predilection for biliary carci-noma as
cholangiocarcinoma may place these individuals at heightened risk
for developing gallbladder cancer.207
4. Congenital biliary abnormalities
An anomalous pancreaticobiliary junction is a rare congenital
anomaly of the biliary tract in which the pancreatic and biliary
ducts join outside the duodenal wall, forming an abnormally long
channel that lies beyond the sphincter of Oddi.208 Such an anomaly
defeats sphincter of Oddi gatekeeper function, poten-tially
allowing pancreatic secretions to regurgitate into the bili-ary
system and gallbladder, and so leading to malignant chang-es in the
mucosa.209 The anomalous pancreaticobiliary junction is more
prevalent in Asian (particularly Japanese) populations and carries
an increased risk of gallbladder cancer at 3% to 18%.183,210 Hence,
prophylactic cholecystectomy is recommended due to the high
frequency of gallbladder carcinoma.
5. Genetic factors
There are undoubtedly genetic and environmental factors that
coincide to become expressed as gallbladder cancer. A family
history of gallbladder cancer is clearly a risk factor.211,212 The
only responsible gene so far identified seems to be that for
apo-lipoprotein B function (the APOB gene), which influences
cho-lesterol handling yet is not associated with gallstones. In
fact, the link between cholesterol gallstones and gallbladder
cancer may relate to an interdependent disposal pathway that
increases the export of both cholesterol and environmental toxins
into bile. As gallbladder cancer is more common in women, such
mutagenic toxins secreted reside longer in the gallbladder due to
stasis from impaired contractility associated with the female
hormone, progesterone. This protracted exposure allows
envi-ronmental carcinogens to then cause malignant transformation,
helping to reconcile the schism of seed versus soil and
incor-porate the predilection to the development of gallstones
(also requiring some gallbladder stasis) and gallbladder
cancer.213
6. Gallbladder polyps
Polypoidal masses of the gallbladder affect 5% of adults and may
be confused with gallbladder cancer.214 Over two-thirds of polyps
are composed of cholesterol esters; the other lesions are adenomas,
leiomyomas or inflammatory polyps. Although occasionally associated
with biliary colic, the vast majority of gallbladder polyps are
asymptomatic, being found incidentally when abdominal imaging is
performed for other purposes. Features that predict malignancy are:
large polyps (>10 mm), a solitary or sessile mass, associated
gallstones, patient age over 50 and most importantly, rapid polyp
growth. Prophylactic cho-lecystectomy is warranted in patients with
polyps that possess such malignant-appearing features.
7. Other lifestyle factors
The association of gallstones with gallbladder cancer likely
explains why some of the traditional risk factors for gallstones
are also risk factors for gallbladder cancer including obesity,
female gender, and multiparity. In over 84,000 men and 97,000 women
included in The Cancer Prevention Study II Nutrition Cohort, the
relative risk of gallbladder cancer was 1.8 (95% confidence
interval [CI], 1.1 to 2.9) in obese men with a BMI of 30.0 to 34.9
compared to men with a normal BMI (18.5 to 24.9). Obese women (BMI,
30.0 to 34.9) had a relative risk of 2.1 (95% CI, 1.6 to 2.9)
compared to women with a normal BMI.215 Overall, obesity has a
relative risk of 1.66 (95% CI, 1.47 to 1.88) for gallbladder
cancer.216 Other lifestyle risks involve cigarette smoking, and
alcohol consumption (in men only).217
CONCLUSION
The prevalence of gallbladder disease at any point in time
-
Stinton LM, et al: Epidemiology of Gallbladder Disease:
Cholelithiasis and Cancer 181
(i.e., prevalence) has advanced with the use of ultrasonographic
surveys as opposed to previous studies based on clinical or
nec-ropsy evidence.2,3 These population surveys have better defined
important risk factors, both unchangeable and modifiable. The
implications of changing environmental risk factors predict an
increase in the numbers of individuals with gallstones. An aging
population plus the rising epidemic of obesity and the metabolic
syndrome are certain to aggravate the frequency and complications
of gallstone disease. Identifying risk factors that can be altered
(i.e., extreme obesity, rapid weight loss, sedentary lifestyle, and
key dietary factors) should provide an opportunity to prevent
cholelithiasis. Several risk factors for gallstones are also
implicated in the pathogenesis of gallbladder cancer. Al-though the
frequency of gallbladder cancer is relatively low in the U.S., if
the incidence of gallstones rises, gallbladder cancer most likely
will also increase.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was
reported.
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